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Updated: Jun 14, 2025
Isogenic Kidney Glomerulus Chip Engineered from Human Induced Pluripotent Stem Cells
Published on: November 4, 2022
Engineered human iPS cell models reveal altered podocytogenesis and glomerular capillary wall in CHD-associated SMAD2
Insights
Congenital heart disease (CHD) linked SMAD2 gene variants disrupt kidney development. This study reveals how these SMAD2 mutations impair kidney cell formation and function, potentially explaining multi-organ issues in CHD patients.
Area of Science:
- Developmental Biology
- Genetics
- Nephrology
Background:
- Congenital heart disease (CHD) is linked to multi-organ impairments.
- Patients with CHD and SMAD2 variants often show kidney issues like glomerulosclerosis and albuminuria.
- The direct impact of SMAD2 variants on kidney development remains unclear.
Purpose of the Study:
- To investigate the role of pathogenic SMAD2 variants in kidney podocytogenesis.
- To determine if SMAD2 variants associated with CHD directly affect kidney cell fate and function.
- To model kidney development using human induced pluripotent stem cells (iPSCs) and organ-on-a-chip systems.
Main Methods:
- Engineered human iPSCs to model SMAD2 variants.
- Utilized organ-on-a-chip systems, including a glomerulus-on-a-chip platform.
- Differentiated iPSCs to examine kidney cell lineage development and podocyte formation.
Main Results:
- Abrogation of SMAD2 altered mesoderm and intermediate mesoderm (IM) cell patterning.
- Mutant podocytes derived from IM cells failed to develop proper arborizations and interdigitations.
- The glomerulus-on-a-chip model showed significant proteinuria, mirroring clinical observations.
Conclusions:
- CHD-associated SMAD2 mutations directly impact kidney tissue malformation during development.
- SMAD2 plays a critical role in kidney cell lineage specification and podocyte differentiation.
- This research offers insights into the mechanisms underlying kidney defects in CHD and potential therapeutic targets.
Abstract:
Early developmental programming involves extensive cell lineage diversification through shared molecular signaling networks. Clinical observations of congenital heart disease (CHD) patients carrying SMAD2 genetic variants revealed correlations with multi-organ impairments at the developmental and functional levels. For example, many CHD patients present with glomerulosclerosis, periglomerular fibrosis, and albuminuria. Still, it remains largely unknown whether SMAD2 variants associated with CHD can directly alter kidney cell fate, tissue patterning, and organ-level function. To address this question, we engineered human iPS cells (iPSCs) and organ-on-a-chip systems to uncover the role of pathogenic SMAD2 variants in kidney podocytogenesis. Our results show that abrogation of SMAD2 causes altered patterning of the mesoderm and intermediate mesoderm (IM) cell lineages, which give rise to nearly all kidney cell types. Upon further differentiation of IM cells, the mutant podocytes failed to develop arborizations and interdigitations. A reconstituted glomerulus-on-a-chip platform exhibited significant proteinuria as clinically observed in glomerulopathies. This study implicates CHD-associated SMAD2 mutations in kidney tissue malformation and provides opportunities for therapeutic discovery in the future.
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